Synthesis device of everolimus impurities

Abstract

The utility model relates to the technical field of pharmacy, in particular to a synthesis device of everolimus impurities. Comprising a reaction kettle, a stirring mechanism arranged in the reaction kettle and a driving mechanism connected with the stirring mechanism, the reaction kettle is of a three-layer nested structure, and the reaction kettle comprises a reaction kettle body arranged on the inner layer, a temperature adjusting interlayer arranged on the periphery of the reaction kettle body and an outer concentration cavity arranged on the periphery of the temperature adjusting interlayer; the bottom of the outer concentration cavity is communicated with the bottom of the reaction kettle body, a flow control valve is arranged at the communication position, the outer concentration cavity is connected with a condenser through a gas conveying pipe and connected with a vacuum pump through an exhaust pipe, and reaction liquid in the reaction kettle body flows into the outer concentration cavity through the flow control valve under regulation and control of the vacuum pump. And reduced-pressure heating concentration is realized in the outer concentration cavity. The problem of meeting diversified requirements of different reaction steps is solved, and the synthesis efficiency of the everolimus impurity is improved.

Description

TECHNICAL FIELD

[0001] The utility model relates to pharmaceutical technology field especially is involved in a kind of synthesis device of everolimus impurity. BACKGROUND

[0002] Everolimus is a kind of commonly used antitumor drug at home and abroad, and the research and production of everolimus need a large amount of impurity reference substance, and directional synthesis of the impurity has high application value, and the research of its impurity is crucial to drug quality control, analysis method development etc..At present, the synthesis process of everolimus impurity, the generality of equipment is poor, reaction step is more, and existing equipment cannot satisfy the diversification demand of different reaction steps.The existing synthesis device is difficult to control reaction temperature, material mixing degree, concentration chromatography purification, extraction and other key processes, which limits the quality and efficiency of everolimus impurity synthesis, therefore, a kind of everolimus impurity synthesis device is needed to improve the synthesis efficiency of everolimus impurity. UTILITY MODEL CONTENTS

[0003] In order to solve the problem of meeting the diversification demand of different reaction steps and improving the synthesis efficiency of everolimus impurity, the utility model provides a kind of synthesis device of everolimus impurity.

[0004] The utility model provides a kind of synthesis device of everolimus impurity, including reaction kettle, the stirring mechanism of being arranged in reaction kettle, with the drive mechanism being connected with stirring mechanism, the reaction kettle is three-layer nested structure, the reaction kettle includes the reaction kettle body of being placed in inner layer, the temperature-adjusting interlayer of being arranged in the outer periphery of reaction kettle body, the outer concentration cavity of being arranged in the outer periphery of temperature-adjusting interlayer, the bottom of outer concentration cavity is communicated with the bottom of reaction kettle body, and control valve is arranged at the communicating portion, the outer concentration cavity is connected with condenser by gas conveying pipe, the outer concentration cavity is connected with vacuum pump by exhaust pipe, reaction liquid in reaction kettle body flows into outer concentration cavity under the regulation of vacuum pump by control valve, and realizes reduced pressure heating concentration in outer concentration cavity.

[0005] Further, the bottom of outer concentration cavity is equipped with three-way discharge valve pipe, one end of three-way discharge valve pipe is connected with chromatography mechanism by discharge pipe, chromatography mechanism includes liquid transfer end and liquid outlet end, liquid transfer end is connected with reaction kettle body by liquid transfer pipe, discharge pump is arranged on discharge pipe, suction pump is arranged on liquid transfer pipe, liquid outlet end is equipped with liquid outlet valve, liquid transfer pipe is equipped with liquid transfer valve.

[0006] Further, one end of three-way discharge valve pipe communicating discharge pipe is equipped with discharge valve, the other end of three-way discharge valve pipe is equipped with discharge valve.

[0007] Further, temperature-adjusting interlayer is connected with liquid inlet pipe and liquid outlet pipe, heating mechanism is arranged in temperature-adjusting interlayer, and heating mechanism is electric heating wire.

[0008] Further, the stirring mechanism comprises a stirring rod, and the driving mechanism comprises a motor, and a power end of the motor is fixedly connected with the stirring rod.

[0009] Further, the stirring mechanism further comprises a connecting disc arranged on the stirring rod, and stirring blades are arranged on the connecting disc in a circumferential direction.

[0010] Further, the stirring rod is provided with a connecting rod, the connecting rod is connected with a scraper, and the scraper slides along the inner wall of the reaction kettle body.

[0011] Further, the bottom of the concentration outer cavity is communicated with the bottom of the reaction kettle body through a columnar structure, and an observation window is arranged on the columnar structure.

[0012] Further, the condenser is provided with a spiral condenser pipe, an outer wall is provided with a cooling jacket, the spiral condenser pipe is provided with a suction nozzle, the suction nozzle is connected with a gas conveying pipe, the cooling jacket is provided with a cooling water inlet pipe and a cooling water outlet pipe, and the gas conveying pipe is provided with a gas conveying valve.

[0013] Further, the upper end of the reaction kettle body is provided with a feeding port one, and the upper end of the outer concentration cavity is provided with a feeding port two.

[0014] In conclusion, the utility model has the beneficial technical effects as follows:

[0015] 1. The utility model provides a kind of synthesis device of everolimus impurity, reaction kettle adopts three-layer nested structure, temperature-adjusting interlayer is connected with liquid inlet pipe and liquid outlet pipe, and built-in electric heating wire, can adjust reaction temperature, meet the temperature demand of different reaction steps.Outer concentration cavity is communicated with the bottom of reaction kettle body, through the regulation and control of vacuum pump and flow control valve, reaction liquid can flow into outer concentration cavity and realize reduced pressure heating concentration, because the wall of outer concentration cavity is relatively thin, and the contact area with temperature-adjusting interlayer is larger, greatly improve concentration efficiency, through the structure that the bottom of outer concentration cavity is communicated with the bottom of reaction kettle body, extraction separation can also be realized.

[0016] 2. The utility model provides a kind of synthesis device of everolimus impurity, stirring mechanism includes stirring blade and scraper, not only can make material fully mix, but also can prevent material from adhering to reaction kettle inner wall, guarantee the uniformity of reaction.

[0017] 3. The utility model provides a kind of synthesis device of everolimus impurity, the device integrates reaction, temperature control, stirring, concentration, chromatography, extraction and multiple key processes, meet the diversification demand of different reaction steps in the synthesis process of everolimus impurity, avoid the inconvenience and loss caused by frequent material transfer, greatly improve the synthesis efficiency of everolimus impurity. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1It is a structural schematic view of the synthesis device of the everolimus impurity.

[0019] Figure 2 It is a structural schematic view of the stirring mechanism.

[0020] Figure 3 It is an embodiment of the utility model Figure 1 The partial close -up view of A.

[0021] Figure 4 It is a structural schematic view of the condenser.

[0022] 1, reaction kettle;101, reaction kettle body;102, temperature adjusting interlayer;103, liquid inlet pipe;104, liquid outlet pipe;105, heating mechanism;106, outer concentration cavity;107, observation window;108, feeding port one;109, feeding port two;110, flow control valve;2, stirring mechanism;201, stirring rod;202, connecting disc;203, stirring paddle;204, connecting rod;205, scraper;3, motor;4, condenser;401, gas conveying pipe;402, gas conveying valve;403, spiral condenser pipe;404, cooling jacket;405, suction nozzle;406, cooling water inlet pipe;407, cooling water outlet pipe;5, vacuum pump;501, air suction pipe;6, chromatography mechanism;601, three-way discharge valve pipe;602, discharge valve;603, liquid discharge pipe;604, liquid discharge pump;605, liquid discharge valve;606, liquid outlet valve;607, liquid transfer pipe;608, suction pump;609, liquid transfer valve. Specific implementation

[0023] The utility model makes further detailed description in combination with the drawings.

[0024] Embodiment 1

[0025] Referring Figure 1 , the synthesis device of the everolimus impurity of this embodiment includes reaction kettle 1, the stirring mechanism 2 that is set up in the reaction kettle 1, the drive mechanism that is connected with the stirring mechanism 2, the reaction kettle 1 is three-layer nested structure, the reaction kettle 1 includes the reaction kettle body 101 that is placed in the inner layer, the temperature adjusting interlayer 102 that is set up at the outer periphery of the reaction kettle body 101, the outer concentration cavity 106 that is set up at the outer periphery of the temperature adjusting interlayer 102, the bottom of the outer concentration cavity 106 is communicated with the bottom of the reaction kettle body 101, and is equipped with flow control valve 110 at the communicating place, the outer concentration cavity 106 is connected with condenser 4 through gas conveying pipe 401, the outer concentration cavity 106 is connected with vacuum pump 5 through air suction pipe 501, the reaction liquid in the reaction kettle body 101 is flowed into the outer concentration cavity 106 under the regulation of vacuum pump 5 through flow control valve 110, and realizes the reduced pressure heating concentration in the outer concentration cavity 106.

[0026] The reaction kettle 1 adopts a three-layer nested structure, the innermost layer is the reaction kettle body 101, which is the core area of raw material mixing and reaction; the middle layer is the temperature adjusting interlayer 102, which can quickly switch different temperature media through the connection of the liquid inlet pipe 103 and the liquid outlet pipe 104, and is internally provided with an electric heating wire to realize temperature regulation; the outermost layer is the outer concentration cavity 106, which is connected with the bottom of the reaction kettle body 101 through the communication port provided with the flow control valve 110 at the bottom, which can accurately control the flow of the reaction liquid, and the outer concentration cavity 106 is also connected with the gas conveying pipe 401 and the gas extraction pipe 501 respectively, the gas conveying pipe 401 leads to the condenser 4, and the gas extraction pipe 501 is connected with the vacuum pump 5, so as to realize the concentration of pressure reduction heating, wherein the flow control valve 110 is an electromagnetic valve.

[0027] The bottom of the outer concentration cavity 106 is provided with a three-way discharge valve 602 pipe 601, one end of the three-way discharge valve 602 pipe 601 is connected with a chromatography mechanism 6 through a liquid discharge pipe 603, the chromatography mechanism 6 includes a liquid transfer end and a liquid outlet end, the liquid transfer end is connected with the reaction kettle body 101 through a liquid transfer pipe 607, a liquid discharge pump 604 is arranged on the liquid discharge pipe 603, a suction pump 608 is arranged on the liquid transfer pipe 607, the liquid outlet end is provided with a liquid outlet valve 606, and the liquid transfer pipe 607 is provided with a liquid transfer valve 609.

[0028] Referring to Figure 1 , one end of the three-way discharge valve 602 pipe 601 connected with the liquid discharge pipe 603 is provided with a liquid discharge valve 605, and the other end of the three-way discharge valve 602 pipe 601 is provided with a discharge valve 602.

[0029] The bottom of the outer concentration cavity 106 is provided with a three-way discharge valve 602 pipe 601, one end of the three-way discharge valve 602 pipe 601 is connected with a chromatography mechanism 6 through a liquid discharge pipe 603, the chromatography mechanism 6 includes a liquid transfer end and a liquid outlet end, the liquid transfer end is connected with the reaction kettle body 101 through a liquid transfer pipe 607, a liquid discharge pump 604 is arranged on the liquid discharge pipe 603, a suction pump 608 is arranged on the liquid transfer pipe 607, the liquid outlet end is provided with a liquid outlet valve 606, and the liquid transfer pipe 607 is provided with a liquid transfer valve 609.

[0030] Referring to Figure 1 , the temperature adjusting interlayer 102 is connected with the liquid inlet pipe 103 and the liquid outlet pipe 104, and the temperature adjusting interlayer 102 is provided with a heating mechanism 105, and the heating mechanism 105 is an electric heating wire.

[0031] Referring to Figure 2 , the stirring mechanism 2 includes a stirring rod 201, and the driving mechanism includes a motor 3, and the power end of the motor 3 is fixedly connected with the stirring rod 201.

[0032] With reference to Figure 2 The stirring mechanism 2 further comprises a connecting disc 202 arranged on the stirring rod 201, and stirring blades 203 arranged circumferentially on the connecting disc 202.

[0033] The stirring rod 201 is provided with a connecting rod 204, and a scraper 205 is connected to the connecting rod 204, and the scraper 205 slides along the inner wall of the reaction kettle body 101.

[0034] The stirring mechanism 2 is arranged in the reaction kettle body 101, and the stirring rod 201 is driven by the motor 3 in the driving mechanism, and the power end of the motor 3 is fixedly connected with the stirring rod 201, so as to ensure the stability of the stirring action. The stirring blades 203 make the materials fully mixed in the reaction kettle body 101, thereby improving the reaction efficiency. In addition, the scraper 205 is connected to the connecting rod 204 on the stirring rod 201, and the scraper 205 slides along the inner wall of the reaction kettle body 101, thereby effectively preventing the materials from adhering to the kettle wall.

[0035] With reference to Figure 3 The bottom of the concentration outer cavity is communicated with the bottom of the reaction kettle body 101 through a columnar structure, and the columnar structure is provided with an observation window 107. The observation window 107 is used for observing the extraction and separation situation.

[0036] With reference to Figure 4 The condenser 4 is internally provided with a spiral condenser pipe 403, and an outer wall is provided with a cooling jacket 404. The spiral condenser pipe 403 is provided with a suction nozzle 405, the suction nozzle 405 is connected with a gas conveying pipe 401, the cooling jacket 404 is provided with a cooling water inlet pipe 406 and a cooling water outlet pipe 407, and the gas conveying pipe 401 is provided with a gas conveying valve 402.

[0037] By adjusting the flow of cooling water, the condensation effect can be controlled, and the gas conveying valve 402 on the gas conveying pipe 401 is used for controlling the gas flow.

[0038] The concentration outer cavity is communicated with the bottom of the reaction kettle body 101 through a columnar structure, and the columnar structure is provided with an observation window 107. The operator can observe the extraction and separation situation in real time when the reaction liquid is transferred.

[0039] With reference to Figure 1 The upper end of the reaction kettle body 101 is provided with a feeding port one 108, and the upper end of the outer concentration cavity 106 is provided with a feeding port two 109, so as to facilitate the addition of various raw materials and reagents.

[0040] Example 2

[0041] The difference between this embodiment and example 1 is that this embodiment provides a synthesis method of an everolimus impurity.

[0042] Step one:

[0043] Raw material preparation: take 200 kg of sirolimus, measure 1200 L of tetrahydrofuran, slowly add sirolimus from feeding port one 108 into tetrahydrofuran in the reaction kettle body 101, start the stirring mechanism 2, set the appropriate stirring speed, and carry out preliminary stirring to ensure that sirolimus is completely dissolved.

[0044] Reaction process: slowly pass the low-temperature cooling liquid (such as a mixture of liquid nitrogen and ethanol) into the temperature control layer 102 through the liquid inlet pipe 103 at a controlled flow rate until the temperature is reduced to -40°C. According to the preset stirring speed and time parameters, start the stirring mechanism 2, and at the same time, add 40 kg of DHP (2-tetrahydropyran) and 1000 kg of PPTs (pyridinium p-toluenesulfonate) from the feeding port one 108. After stirring for a period of time, stop stirring, and use the temperature control system to maintain the cooling temperature overnight to ensure that the reaction is fully carried out.

[0045] Subsequent processing: after the reaction is completed, the low-temperature cooling liquid is discharged through the liquid outlet pipe 104, the control valve 110 is slowly opened, and based on the principle of the communicating vessel, the reaction liquid in the reaction kettle body 101 flows into the outer concentration cavity 106. Start the vacuum pump 5 to make more reaction liquid flow into the outer concentration cavity 106, and then close the control valve 110. Pass hot water into the temperature control layer 102 through the liquid inlet pipe 103, and start the electric heating wire to heat. Use the pressure sensor and temperature sensor to monitor the pressure and temperature in the outer concentration cavity 106 in real time to ensure that the solvent in the reaction liquid is smoothly removed. Open the control valve 110 again and continue heating and concentrating. Because the wall of the outer concentration cavity 106 is relatively thin, the contact area with the temperature control layer 102 is increased, and the concentration efficiency is significantly improved. Then, open the liquid discharge valve 605, and use the liquid discharge pump 604 to discharge the concentrated residue through the three-way discharge valve 602 pipe 601 to the chromatography mechanism 6. The chromatography mechanism 6 uses silica gel chromatography, and the eluent is prepared according to the accurate proportion of 2V cyclohexane / 1V ethyl acetate. The flow rate of the eluent is accurately controlled by using the flow control device, and the eluate is collected. The eluate is transported again to the reaction kettle body 101 through the liquid transfer pipe 607 by using the suction pump 608, and the above-mentioned heating and concentrating method is used again to obtain white solids, which are discharged through the discharge valve 602 for the next step reaction.

[0046] Step two:

[0047] Raw material preparation: measure 400 L of DMF (N,N-dimethylformamide), and slowly add the white solids obtained in step one into the DMF in the reaction kettle body 101 from the feeding port one 108, and start the stirring mechanism 2 to ensure that the white solids are completely dissolved.

[0048] Reaction process: Add ice water into the temperature control interlayer 102, monitor the temperature in the reaction kettle body 101 in real time by using the temperature sensor, start the stirring mechanism 2, and stir according to the preset stirring speed and time parameters. Add 24 kg of anhydrous potassium carbonate and 40 kg of 2-bromoethoxy tetrahydro pyrrole from the feeding port one 108, keep the temperature in the set range, and heat for 6 h.

[0049] Subsequent processing: After the reaction is completed, add 400 L of ice water into the reaction kettle body 101 through the metering device, and continue to stir for 30 min. Add the extraction liquid (dichloromethane) from the feeding port one 108 according to the preset addition amount, start the stirring mechanism 2, and after the stirring is completed, stand for a period of time to make the solution stratify. Slowly open the flow control valve 110, accurately adjust the extraction liquid flowing into the outer concentration cavity 106 through the vacuum pump 5, make the lower heavy liquid (the dichloromethane layer containing the target product) flow into the outer concentration cavity 106, close the flow control valve 110, and realize the effective separation of the clear liquid and the heavy liquid. Add anhydrous sodium sulfate in the outer concentration cavity 106 through the feeding port two 109, stir uniformly by using the stirring device, and dry overnight. Finally, heat and concentrate the concentrated residue by using the heating mechanism 105. In this extraction process, the density of dichloromethane is greater than that of water, so the dichloromethane layer (containing the target product) is the lower heavy liquid, and the lower heavy liquid needs to be reserved. The purpose of adding anhydrous sodium sulfate is to remove the water in the organic layer. Anhydrous sodium sulfate can combine with water to form hydrate, thereby playing a drying role.

[0050] Step three:

[0051] Raw material preparation: discharge the reaction product of step two through the discharge valve 602, measure 400 L of methanol, and add the two into the reaction kettle body 101 from the feeding port one 108, and at the same time, start the stirring mechanism 2 and set the appropriate stirring speed to ensure that the reaction product is fully dissolved in the methanol.

[0052] Reaction process: stir at room temperature according to the preset stirring speed, accurately control the introduction of 100 L of saturated hydrogen chloride methanol solution through the gas flow meter, and continue to stir at room temperature for 4 h.

[0053] Subsequent processing: 400 L of dichloromethane and 200 L of ice water are added to the reaction kettle body 101, and the liquid separation operation is performed by using the similar method of step two, through the flow control valve 110, vacuum pump 5, and liquid level sensor, etc. Anhydrous sodium sulfate is added, stirred uniformly, and dried overnight, and finally the same heating and concentration method as before is used, and the heating mechanism 105 and temperature and pressure monitoring device are used for heating and concentration. The residue is discharged through the three-way valve to the chromatography mechanism 6 for silica gel column chromatography, the eluent is prepared according to the accurate proportion of 2V cyclohexane / 1V ethyl acetate, the flow rate of the eluent is accurately controlled by using the flow control device, and the eluate is collected. The eluate is transported to the reaction kettle body 101 again through the liquid transfer pipe 607 by using the suction pump 608, and the above-mentioned heating and concentration method is used again to obtain a white solid, which is discharged through the discharge valve 602, and the whole reaction is completed. The theoretical output is about 64 kg of everolimus impurities, and the purity is about 98%.

[0054] The above are preferred embodiments of the present application, and do not limit the protection scope of the present application, so: any equivalent changes made according to the structure, shape, principle of the present application should be covered within the protection scope of the present application.

Claims

1. An apparatus for synthesizing everolimus impurities, characterized in that, The reactor includes a reactor vessel (1), a stirring mechanism (2) disposed within the reactor vessel (1), and a driving mechanism connected to the stirring mechanism (2). The reactor vessel (1) has a three-layer nested structure. The reactor vessel (1) includes a reactor body (101) placed in the inner layer, a temperature-regulating jacket (102) disposed on the outer periphery of the reactor body (101), and an outer concentration chamber (106) disposed on the outer periphery of the temperature-regulating jacket (102). The bottom of the outer concentration chamber (106) is connected to the reactor body (101). The bottom of the reactor vessel (101) is connected, and a flow control valve (110) is provided at the connection. The external concentration chamber (106) is connected to a condenser (4) through a gas supply pipe (401). The external concentration chamber (106) is connected to a vacuum pump (5) through a gas extraction pipe (501). The reaction liquid in the reactor vessel (101) flows into the external concentration chamber (106) through the flow control valve (110) under the regulation of the vacuum pump (5), and pressure reduction heating concentration is achieved in the external concentration chamber (106).

2. The apparatus for synthesizing everolimus impurities according to claim 1, characterized in that, The bottom of the external concentration chamber (106) is provided with a three-way discharge valve (602) pipe (601). One end of the three-way discharge valve (602) pipe (601) is connected to a chromatography mechanism (6) through a drain pipe (603). The chromatography mechanism (6) includes a liquid transfer end and a liquid outlet end. The liquid transfer end is connected to the reactor body (101) through a liquid transfer pipe (607). A drain pump (604) is provided on the drain pipe (603). A suction pump (608) is provided on the liquid transfer pipe (607). A liquid outlet valve (606) is provided on the liquid outlet end. A liquid transfer valve (609) is provided on the liquid transfer pipe (607).

3. The apparatus for synthesizing everolimus impurities according to claim 2, characterized in that, The three-way discharge valve (602) pipe (601) is connected to the drain pipe (603) at one end with a drain valve (605), and the three-way discharge valve (602) pipe (601) is connected to a discharge valve (602).

4. The apparatus for synthesizing everolimus impurities according to claim 3, characterized in that, The temperature-regulating jacket (102) is connected to an inlet pipe (103) and an outlet pipe (104). The temperature-regulating jacket (102) is provided with a heating mechanism (105), which is an electric heating wire.

5. The apparatus for synthesizing everolimus impurities according to claim 4, characterized in that, The stirring mechanism (2) includes a stirring rod (201), and the driving mechanism includes a motor (3), the power end of the motor (3) being fixedly connected to the stirring rod (201).

6. The apparatus for synthesizing everolimus impurities according to claim 5, characterized in that, The stirring mechanism (2) further includes a connecting plate (202) disposed on the stirring rod (201) and stirring blades (203) disposed circumferentially on the connecting plate (202).

7. The apparatus for synthesizing everolimus impurities according to claim 6, characterized in that, The stirring rod (201) is provided with a connecting rod (204), and the connecting rod (204) is connected to a scraper (205), which slides along the inner wall of the reactor body (101).

8. The apparatus for synthesizing everolimus impurities according to claim 7, characterized in that, The bottom of the concentration chamber is connected to the bottom of the reactor body (101) through a columnar structure, and the columnar structure is provided with an observation window (107).

9. The apparatus for synthesizing everolimus impurities according to claim 8, characterized in that, The condenser (4) has a built-in spiral condenser tube (403) and a cooling jacket (404) on its outer wall. The spiral condenser tube (403) is provided with a suction nozzle (405), which is connected to the gas delivery pipe (401). The cooling jacket (404) is provided with a cooling water inlet pipe (406) and a cooling water outlet pipe (407). The gas delivery pipe (401) is provided with a gas delivery valve (402).

10. The apparatus for synthesizing everolimus impurities according to claim 9, characterized in that, The upper end of the reactor body (101) is provided with a feeding port one (108), and the upper end of the external concentration chamber (106) is provided with a feeding port two (109).

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